The co-activators CBP and p300 regulate transcription of genes involved in the control of the cell cycle and differentiation. Although little is known of the functions performed by these factors in the differentiation of keratinocytes, the applicant provides preliminary data, using viral oncogenes, that CBP/p300 play an important role. The E6 protein (E6.16) from human papillomavirus type 16 inhibits keratinocyte differentiation and the applicant has recently shown that E6.16 protein binds to both CBP and p300 in three distinct regions (C/H1, C/H3, and a C-terminal domain). The interaction inhibits the ability of CBP-p300 to co-activate transcription factors that bind to the same domains. Importantly, the applicant has identified mutations of E6.16 that bind single regions, which can be used to investigate the function of individual domains without disrupting other functions of CBP/p300. The applicant proposes to use these mutant proteins to investigate the role of CBP/p300 in keratinocyte differentiation, to determine which domains of the co-activators are required for controlled differentiation, and to study if both CBP and p300 are necessary. Known targets of CBP/p300, whose function has been implicated in keratinocyte differentiation will be studied, and novel targets of CBP/p300 will be identified.